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Regulation of beta-cell homeostasis by DNA methylation and hydroxymethylation.

通过 DNA 甲基化和羟甲基化调节 β 细胞稳态。

基本信息

批准号：
10557897
负责人：
Sangeeta Dhawan
金额：
$ 43.25万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557897
关键词：
Address Affect Age Animals Antioxidants Ascorbic Acid Beta Cell Cell Cycle Cell Differentiation process Cell physiology Cells Citric Acid Cycle Complex DNA DNA Methylation DNA Modification Methylases DNMT3a Data Defect Development Diabetes Mellitus Diabetic mouse Disease Disease Progression Disease model Embryo Endocrine Environment Environmental Risk Factor Enzymes Epigenetic Process Equilibrium Exposure to Failure Functional disorder Glucose Goals Growth and Development function Health Homeostasis Human Hydroxylation Impairment Insulin Insulin-Dependent Diabetes Mellitus Link Maps Mediating Metabolic Metabolism Methods Mus Nature Neonatal Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pancreas Pattern Persons Phenotype Polycomb Predisposition Public Health Publishing Regulation Regulatory Pathway Rejuvenation Research Role Shapes Stimulus Testing Tissues United States Variant Work age related alpha ketoglutarate antagonist beta cell replacement betacell therapy cofactor defined contribution demethylation diabetes mellitus therapy diabetes pathogenesis diabetes risk diabetic endocrine pancreas development epigenetic profiling epigenome functional loss genome-wide improved insulin secretion interest islet methylation pattern mouse genetics mouse model novel preservation progenitor response self-renewal stem cells therapeutically effective type I and type II diabetes

项目摘要

PROJECT SUMMARY/ABSTRACT Diabetes has become a major public health crisis, afflicting nearly 30 million people in the United States, and these numbers continue to rise at an alarming rate. Both type 1 and type 2 diabetes result from insulin insufficiency, in large part due to loss of functional beta-cells. Significant research efforts are currently focused on understanding beta-cell failure in diabetes, and developing effective therapeutic approaches to replenishing the beta-cell deficit in diabetes. Despite significant advances in these aspects, challenges remain in development of effective beta-cell therapies, primarily due to gaps in our current understanding of mechanisms that regulate normal beta-cell development, function, and growth. Our recent work has identified DNA methylation as a pivotal epigenetic mechanism that regulates beta-cell identity and function. Moreover, we found that DNA methylation patterns defining functional beta-cell phenotype are disrupted in the diabetic beta-cells, suggesting dynamic nature of DNA methylation. Our preliminary studies indicate that dynamic remodeling of DNA methylation (5- methylcytosine; 5mC) via its conversion to a hydroxylated form (5-hydroxymethylcytosine; 5hmC) is essential for beta-cell differentiation, function, and adaptive response. We hypothesize that stage-specific, appropriate patterning of 5mC and 5hmC is critical for beta-cell homeostasis, and is disrupted in diabetes leading to beta- cell failure. Thus, we seek to determine how enzymatic regulation of the balance between 5mC and 5hmC governs functional beta-cell mass and affects diabetes susceptibility. We will employ mouse genetics, disease models, human islet studies, and state-of-the-art genome wide epigenetic profiling methods to address the following aims: In Specific Aim 1, we aim to establish the requirement of 5mC and 5hmC patterning in differentiation of beta-cells from progenitors. Specific Aim 2 seeks to define the contribution of dynamic remodeling of 5mC and 5hmC patterns in beta-cell replication and adaptive capacity. In Specific Aim 3, we address if and how environmental factors like oxidative stress and metabolite variation can disrupt the beta-cell 5mC 5hmC landscape to drive beta-cell failure, and diabetes. The proposed studies will delineate a novel regulatory module that governs beta-cell development and growth, and establish a fundamental regulatory paradigm that link beta-cell environment, metabolism and epigenome. Our work is likely to have a broad and significant impact by providing novel clues to promote beta- cell differentiation, function, and expansion towards strategies aimed at beta-cell rejuvenation and replacement for diabetes therapy.

项目总结/摘要糖尿病已成为一个重大的公共卫生危机，困扰着美国近3000万人，这些数字继续以惊人的速度上升。1型和2型糖尿病都是由胰岛素引起的这在很大程度上是由于功能性β细胞的丧失。目前主要的研究工作集中在了解糖尿病中的β细胞衰竭，并开发有效的治疗方法，糖尿病中的β细胞缺陷。尽管在这些方面取得了重大进展，有效的β细胞疗法，主要是由于我们目前对调控机制的理解存在差距，正常的β细胞发育、功能和生长。我们最近的工作已经确定DNA甲基化是调节β细胞身份和功能的表观遗传机制。此外，我们发现DNA甲基化在糖尿病β细胞中，定义功能β细胞表型的模式被破坏，这表明动态 DNA甲基化的本质我们的初步研究表明，DNA甲基化的动态重塑（5- 甲基胞嘧啶（5 mC）通过其转化为羟基化形式（5-羟甲基胞嘧啶; 5 hmC）是必不可少的 β细胞分化、功能和适应性反应。我们假设特定阶段的，适当的 5 mC和5 hmC的模式对于β细胞稳态是至关重要的，并且在糖尿病中被破坏，导致β- 细胞故障。因此，我们试图确定酶如何调节5 mC和5 hmC之间的平衡，控制功能性β细胞群并影响糖尿病易感性。我们将利用老鼠的遗传学，疾病模型，人类胰岛研究，以及最先进的全基因组表观遗传分析方法，以解决以下目标：在具体目标1中，我们的目标是建立5 mC和5 hmC模式的要求，从祖细胞分化β细胞。具体目标2旨在确定动态的贡献 β细胞复制和适应能力中5 mC和5 hmC模式的重塑。在具体目标3中，我们解决环境因素如氧化应激和代谢物变异是否以及如何破坏β细胞 5 mC和5 hmC环境导致β细胞衰竭和糖尿病。拟议的研究将描绘一种新的调控模块，控制β细胞发育，生长，并建立一个基本的监管模式，连接β细胞环境，代谢和表观基因组。我们的工作可能会产生广泛而重大的影响，提供新的线索，以促进β- 细胞分化、功能和扩增，以实现β细胞再生和替代的策略用于糖尿病治疗。